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These two reports from Scott Brady’s and Larry Goldstein’s laboratories are highly significant because they extend the concept that neurodegenerative disease is caused by impaired axonal transport, beyond more common disorders like Alzheimer's, to also include triplet-repeat diseases. The implication is that multiple neurodegenerative diseases may share a similar mechanism. This notion was proposed nearly 20 years ago by Carlton Gajdusek, but many years went by before sufficient technical advances occurred in AD research to provide circumstantial and experimental data supporting this view. Traction in this area began with the demonstration that tau (a microtubule binding protein) was the building block of AD neurofibrillary tangles (NFTs). Also helpful was the resolution of the controversy over the role of NFT formation in AD in 1991 by studies showing that abnormally phosphorylated CNS tau proteins (PHFtau) form the paired helical filaments in AD NFTs, and that excessive phosphorylation of PHFtau reduced its ability to bind microtubules (MTs) and stabilize them in order to support axonal transport. For a detailed review of this research area, see Lee et al., 2001.

Thus, years before it was discovered that loss of tau function was the consequence of tau gene mutations in hereditary tauopathies, such as frontotemporal dementia with parkinsonism linked to chromosome 17 or FTDP-17, it was already appreciated that wild-type tau, when altered by hyperphosphorylaton in AD, sustained a loss of function that might impair axonal transport and so lead to a neurodegenerative disease. This prompted the hypothesis that the generation of PHFtau depletes neurons of tau able to bind microtubules, thereby leading to brain degeneration in AD. This model predicted that: 1) the conversion of tau into PHFtau disrupts MT-based transport as well as perhaps physically “blocking” transport due to accumulations of PHFs in neurons and their processes, and 2) the failure of neurons to export proteins from the cell body to distal processes and to retrieve substances (e.g., trophic factors) internalized at axon terminals compromises neuronal viability. It was proposed that these events would culminate in neuronal dysfunction and degeneration leading to the onset/progression of AD. Remarkably, nearly all of the predictions of this disease model of tau pathology in AD and related tauopathies were validated in the last four years through studies of tau-transgenic mice. Some of these provided experimental proof that neurodegeneration caused by tau aggregation was linked to axonal transport failure (Isihara et al., 1999). Indeed, a consensus in favor of this notion appears to be building and a whole issue of Neuromolecular Medicine was dedicated to this topic last year.

It will be important to confirm and extend the findings described in these two studies, which differ in some details. Both papers conclude that impaired axonal transport plays a significant role in mechanisms underlying neurodegeneration. Significantly, the views proposed in these papers complement and extend the earlier concept of a loss of function and impairment of axonal transport when tau is altered in AD, FTDP-17, and other tauopathies. Specifically, the authors of both of these Neuron papers propose that polyQ species acquire a toxic gain of function that disrupts axonal transport. By adding a toxic gain of function in disease proteins to the more well-documented loss of normal function (as in hyperphosphorylated tau), and linking these abnormalities to impaired axonal transport, these two studies open up bold new avenues for advancing insights into mechanisms of neurodegenerative disease. All of this could have substantial implications for the discovery of new and better therapies for AD and other less common neurodegenerative diseases such as Huntington’s, FTDP-17, other tauopathies, and related disorders.